Cancer is a serious hazard to human life and health. With the changes of external factors such as environmental pollution, the number of cancer cases is rising year by year. According to World Health Organization statistics, about 10 million tumor patients are diagnosed worldwide each year currently, and 7 million people die of cancer related diseases, therefore, malignant tumor has become human's second largest killer which is second only to cardiovascular disease.
Protein kinase (PKs), a kind of enzyme, catalyzes phosphorylation of hydroxyl on tyrosine, serine, and threonine residues through the transfer of the end of ATP (γ) phosphate. Through signal transduction pathways, these enzymes regulate cell growth, differentiation and proliferation. Therefore, all aspects of cell cycle are dependent on the activity of PKs substantially. Furthermore, PKs abnormal activity is associated with the host of disease, ranging from relatively non-life threatening diseases (e.g.: psoriasis) to extremely fatal diseases (e.g., glioblastoma). Protein kinases include two types: Protein tyrosine kinase (PTK) and Serine-threonine kinase (STK).
One of the main aspects of PTK activity is to participate as cell-surface protein growth factor receptor. The growth factor receptor turns into an activated form, which interacts with the protein on the inner surface of cell membrane, through combining with growth factor ligand. It leads to phosphorylation of receptor and other protein tyrosine residue, and the formation of multiple cytoplasmic signaling molecule complexes which affects cell reaction, such as division (proliferation), differentiation, growth, metabolism etc.
Growth factor receptor with PTK activity is called receptor tyrosine kinase (RTK), which includes a big family of transmembrane receptor with multiple biological activities. Met is one of the members of this family, and is often referred to as c-Met or human hepatocyte growth factor receptor tyrosine kinase (hHGFR). As a kind of oncogene, the overpass or down regulation of c-Met lead to tumor growth and invasion. Therefore, the expression of c-Met is believed to play a role in tumor cell growth and migration in the early. Stimulated by ligand HGF (also known as Scatter Factor), c-Met starts a variety of physiological processes containing cell proliferation, motility, differentiation, angiogenesis, wound healing, tissue regeneration, embryonic development. Stimulation of hepatocyte growth factor makes c-Met receptor rapidly internalized via clathrin coated vesicles, and gather around cell nucleus by early transportation of endosomes cavity.
Down regulation, dysregulation, overexpression, mutation of c-Met and/or HGF are associated with uncontrolled cell proliferation and survival, which plays an important role in tumor cell invasion, growth and migration in the early. For this reason, c-Met becomes an important target for anticancer drug development.
Overexpression of c-Met and HGF is related to poor diagnosis of prognosis. There is also evidence to support that HGF, as modifier play a role in cancer occurrence, invasion and metastasis (Review: Herynk, M. H. et al. Radinsky, R. (2000) In Vivo 14:587-596). According to latest data, inhibition of tumor growth, survival and invasion is associated with inhibition of the combination between c-Met and HGF and dimerization of c-Met receptor (Michieli et al. (2004) Cancer Cell 6: 61-73). Patents (US 2005/0037431 and US 2004/0166544) describe the inhibition of c-Met in tumor xenotransplantation mouse model to slow down the growth of tumor, and the specific antibodies for c-Met have been expressed to block the binding of HGF to c-Met. The overexpression of c-Met also occurs in NSCLC, small cell lung cancer, lung cancer cell, breast cancer cell, colon cancer cell and prostate cancer cell. Because c-Met seems to play an important role in the formation of multiple tumors, a variety of strategies have been used to inhibit this receptor tyrosine kinase.
By adjusting the HGF β chain binding to c-Met can affect the regulation of HGF/c-Met signaling pathway. In a particular embodiment, zymogen form HGF β mutant shows 14 times lower affinity to c-Met than to wild-type serine protease form, which suggests that comformational change in singlestranded form of cleaved can lead to best interaction. The extensive mutation of active site of serine protease and the active area of HGF β show that among 38 purified double stranded HGF mutants, there are 17 damaged cells moving or phosphorylated but combining with c-Met. However, the decrease of biological activity is associated with the decrease of c-Met binding to its own mutant HGF β mutant, and the elimination of the dominant role of α-chain binding.
Foretinib (Fig. 1), reported as a quinoline compounds, is an oral c-Met and VEGFR/KDR kinase inhibitor with IC50 values of 0.4 and 0.8 nM to c-Met and KDR, respectively, and has entered phase II clinical research stage. Clinical studies have shown that, Foretinib showed a significant inhibitory effect against a variety of human tumor cell lines (such as human lung cancer cells, human gastric cancer cells, etc.), with an IC50 values of 0.004 μg/mL.

Based on the prior art references, the inventor designs and synthesizes a new serial of quinoline and cinnoline derivatives, which are shown to possess antitumor activity by in vitro screening assay.